2166
J. Org. Chem. 1992,57, 2166-2169
C, 69.28; H, 8.36; N, 5.05. Found: C, 69.09; H, 8.37; N, 5.24. (25,5R)-1-(Carbobenzyloxy)-2-( l-hydroxypropyl)-5methylpyrrolidine (8b). To the trans-amino alcohol Sa (2.7 g, 19 mmol) in water (35 mL) containing NaHC03 (2 g, 24 mmol) was added benzyl chloroformate (3.22 g, 19 "01). The reaction mixture was heated at 80 "C for 24 h, cooled, and extracted with CHC& (3 X 30 mL). To the aqueous layer was added benzyl chloroformate (3.22 g, 19 mmol), and the mixture was heated at 80 "C for 24 h. The reaction mixture was then extracted with CHCl, (3 X 30 mL). The organic layers were joined, dried over Na2S04, concentrated in vacuo, and distilled under reduced pressure to give 8b (3.4 g, 65% yield): bp 175 "C (0.05 mmHg); [aIzD -55" (c = 1.36,chloroform); IR (neat) 3500,1680 cm-l; lH NMR (200 MHz, CDC1,) 6 7.50-7.20 (m, 5 H), 5.20-5.00 (m, 2 H), 4.05-3.70 (m, 2 H), 3.70-3.40 (m, 2 H), 2.70-2.50 (m, 1H), 2.20-1.10 (m, 8 H), 1.15 (d, 1H, J = 7 Hz),1.10 (d, 2 H, J = 7 Hz);l% NMR (50 MHz, CDClJ 6 154.7, 154.2,136.9,128.4,127.9,66.6,62.4,62.1, 57.4,53.5,30.5,30.3,29.60,29.4, 29.1,27.5, 26.9, 20.4, 19.3. Anal. Calcd for C1&IaN03: C, 69.28; H, 8.36; N, 5.05. Found C, 69.28; H, 8.31; N, 5.14. (25,5R)-l-(Carbobenzyloxy)-2-(l-oxop~opyl)-5-methylpyrrolidine (8c). Carbamate 8b (2.77 g, 10 mmol) in CHzClz (30 mL) was added to a solution of pyridinium chlorochromate (3.45 g, 16 "01) in CHzClz(40 mL) at 0 "C. The reaction mixture was stirred at 0 OC for 30 min and then 3 h at room temperature. The solution WBB filtered over Celite, and the solvent was removed in vacuo. The brown residue was triturated with ether (4 X 30 mL). The organic layers were dried over Na&04 and concentrated in vacuo to give & (2.28 g, 83% yield). An analytical sample was distilled under reduced pressure: bp (Kugelrohr) 220 "C (0.1 mmHg); -56" (c = 0.95, chloroform);IR (neat) 1720,1680 mi1;'HNMR (200 MHz, CDClJ 6 9.85-9.75 (m, 0.7 H), 9.55-9.45 (m, 0.3 H), 7.35-7.15 (br s, 5 H), 5.20-5.00 (m, 2 H), 4.10-3.70 (m, 2 H), 2.50-1.40 (m, 6 H), 1.20 (d, 1 H, J = 7 Hz), 1.15 (d, 2 H, J = 7 Hz); 13C NMR (50 MHz, CDC1,) 6 201.5, 201.0, 154.2. 154.1, 136.8, 128.4, 127.8, 66.5, 57.4, 53.6, 41.0, 40.9, 30.5, 29.6, 27.9,27.5, 26.7,26.5, 25.6, 20.4,19.2. Anal. Calcd for Cl6HZ1N0& C, 69.79; H, 7.69; N, 5.09. Found: C, 69.95; H, 7.74; N, 5.10.
l-(Carbobenzyloxy)-2-(3-hydroxydecyl)-5-methylpyrrolidine (8d). Grignard reagent was prepared from Mg (2.9 g, 120 m o l ) and heptyl bromide (19.7 g, 110 mmol) and then added to a cold ( 0 "C) solution of aldehyde 8c (27.5 g, 100 "01) in dry ether (100 mL). The reaction mixture was stirred 30 min at 0 "C then 3 h at room temperature, dropped to ice containing NH4Cl, extracted with ether (4 X 60 mL), dried over Na2S04, concentrated in vacuo, and purified by chromatography on silica gel (eluted with ether:pentane = 6040, R, = 0.2) to give alcohol 8d (22.5 g, 62% yield): bp 204 OC (0.05 mmHg); IR (neat) 3500, 3200,1680 cm-l; lH NMR (200 MHz, CDC13) 6 7.35-7.15 (m, 5 H), 5.15 (s,2 H), 4.10-3.40 (m, 3 H), 2.40-1.70 (m, 4 H), 1.70-1.10 (m, 20 H). 0.95-0.75 (m, 3 H); 13CNMR (50 MHz, CDC1,) 6 155.0, 137.0, 128.3,127.7,66.4, 52.9,37.2,31.7,30.4,29.6,29.2,27.4,26.9, 25.6,22.6, 20.4,19.2,14.0. Anal. Calcd for C23H37N03:C, 73.56; H, 9.93; N, 3.73. Found C, 73.51; H, 9.54; N, 3.39. (25,5R )- l-(Carbobenzyloxy)-2-( t-oxodecy1)-5-met hylpyrrolidine (8e). Alcohol 8d (3.75 g, 10 mmol) in CH2C12(30 mL) was added to a solution of pyridinium chlorochromate (3.45 g, 16 mmol) in CHzClz(40 mL) at 0 "C. The reaction mixture was stirred at 0 "C for 30 min and then 3 h at room temperature. The solution was fitered over Celite and solvent removed in vacuo. The brown residue was triturated with ether (4 X 30 mL). The organic layers were dried over Na2S04,concentrated in vacuo, and purified by chromatography on silica gel (eluted with ether:pentane = 2080, R, = 0.20) to isolate ketone 8e (2.2 g, 59% yield): bp 194 "C (0.05 mmHg); IR (neat) 1700 cm-'; 'H NMR (200 MHz, CDC13) 6 7.45-7.22 (m, 5 H), 5.25-5.03 (m, 2 H), 4.20-3.70 (m, 2 H), 2.55-2.18 (m, 4 H), 2.18-1.80 (m, 2 H), 1.75-1.40 (m, 4 H), 1.38-1.05 (m, 13 H), 1.00-0.80 (m, 3 H); 13CNMR (50 MHz, CDCl3) 6 210.0, 155.1, 137.0, 128.5, 127.9,66.5, 57.5, 57.2, 53.6, 53.3,42.6, 39.9, 31.7, 31.0, 29.9, 29.2, 29.1, 28.5, 27.5, 27.2, 23.7, 22.6, 20.8, 19.6, 14.1. Anal. Calcd for CZ3HsNO3: C, 73.95; H, 9.45; N, 3.75. Found: C, 73.85; H, 9.41; N, 3.74. (35,5B,85)-3-Heptyl-5-methylpyrmlizidine (1). Carbamate 8e (0.75 g, 2 mmol) in methanol (30 mL) was hydrogenated at atmospheric pressure over Pd-B&04 (20 mg).When 2 equiv were absorbed, the solution was filtered and the solvent removed in
0022-3263/92/1957-2166$03.00/0
vacuo. The crude product was distilled under reduced pressure to give 1 (0.36 g, 80% yield): bp 190 "C (25 mmHg); [ a ] = ~+6.60" (c = 2.35, chloroform); IR (neat) 2860,2790 cm-'; 'H NMR (200 MHz, CDCl,) 6 3.65-3.55 (m, 1H), 2.85-2.70 (m, 1H), 2.70-2.55 (m, 1 H), 2.05-1.80 (m, 4 H), 1.55-1.15 (m, 16 H), 1.10 (d, 3 H, J = 7 Hz), 0.85 (t, 3 H, J = 7 Hz); 13C NMR (50 MHz, CDC13) 6 66.5, 64.8,61.6, 37.1,34.4, 32.3,32.0,31.8, 31.6, 29.8, 29.3, 27.2, 22.6, 21.7,13.9. MS (70 ev) m / z 223 (6) [M+'], 208 (9)) 194 (31, 180 (2.5), 166 (l),152 (1.5), 124 (1001, 110 (4), 81 (21), 55 (lo), 31 (7). Anal. Calcd for Cl5HBN C, 80.64, H, 13.09; N, 6.27. Found: C, 80.52; H, 13.08; N, 6.22. The data show 2 % less of the epimeric isomer at C-3.
Acknowledgment. We are grateful to Dr. S. Arseniyasis and Prof. H. P. Husson of the Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, France, for kindly providing the 'H and I3C NMR spectra of synthetic (+)-(35,5R,8S)-3-hepty1-5-methylpyrrolizidine.We are grateful to UCIB (Usines Chimiques d'Ivry-la-Bataille, France) for the generous gift of the (5)-pyroglutamicacid. Registry No. 1,135683-51-1;3,138722-97-1;4b,51693-17-5; 4c, 29266-73-7; 4d,21395-93-7; 6,138722-98-2; 7,138722-99-3; 8a, 138810-07-8;8b, 138810-08-9; 8c, 138723-01-0; 8d, 138723-02-1; 8e, 138723-03-2; 9a, 85921-45-5; 9b, 138723-00-9; 2-acetylbutyrolactone, 517-23-7. Supplementary Material Available: Spectra of 4c, 4d,6, 7, 3, 8a, 8b, 8c, 9b, 8d, 8e,and 1 (27 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can be ordered from the ACS; seen any current masthead page for ordering information.
CsF-Promoted Esterification of Carboxylic Acids. A Practical Alternative to the Diazomethane Method and Direct Conversion of Organotin Carboxylates Tsuneo Sato, Junzo Otera,* and Hitosi Nozaki
Department of Applied Chemistry, Okayama University of Science, Ridai-cho, Okayama 700,Japan Received September 10, 1991
Esterification of carboxylic acids by reaction with alkyl halides is a fundamental transformation in organic synthesis.' Potassium and cesium salts have proved useful for this purpose. Clark et al., in their extensive studies, revealed KF to be effective, but unfortunately, the reaction usually required high temperature (110-130 oC).2 In addition, KF3 and CsHCOt were reported to promote solid-phase peptide synthesis. More recently, Cs2C03was employed in macrolactoni~ation~ and peptide synthesis.s However, little attention has been directed toward CsF' (1) (a) Haslam, E. In Protective Groups in Organic Chemistry; McOmie, J. F. W., Ed.; Plenum: London and New York, 1973; Chapter 5. (b) Greene, T. W. Protective Groups in Organic Synthesis; John Wiley & Sons: New York, 1981; Chapter 5. (c)Haslam, E. Tetrahedron 1980,36, 2409. (2) (a) Clark, J. H.; Emsley, J. J. Chem. SOC.,Dalton Trans. 1975, 2129. (b) Clark, J. H.; Miller,J. M. J. Chem. SOC.,Chem. Commun. 1976, 229. (c) Clark, J. H.; Holland, H. L.; Miller, J. M. Tetrahedron Lett. 1976, 3361. (d) Clark, J. H.; Miller, J. M. J. Am. Chem. SOC.1977,99,498. (e) Clark, J. H.; Miller, J. M. Tetrahedron Lett. 1977,599. (0Clark, J. H.; Emsley, J.; Hoyte, 0. P. A. J. Chem. SOC.,Perkin Trans. I 1977, 1091. (9) Clark, J. H. J. Chem. SOC.,Chem. Commun. 1978, 789. (3) Tam, J. P.; Kent, S. B. H.; Wong, T. W.; Merrifield, R. B. Synthesis .... 1976. 955. --(4) Gisin, B. F. Helv. Chim. Acta 1973,56,1476. (5) Kruizinga, W. H.; Kellog, R. M. J. Am. Chem. SOC.1981,103,5183. - r
(6)Wang, S.-S.;Gisin, B. F.; Winter, D. P.; Makofake, R.; Kulesha, I. D.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1977,42,1286. Lerchen, H.-G.; Kunz, H. Tetrahedron Lett. 1985,26, 5257.
0 1992 American Chemical Society
J. Org. Chem., Vol. 57, No. 7, 1992 2167
Notes Table I. Reaction of Benzoic Acid with Ethyl Iodide in the Presence of Alkali Metal Fluoride" PhCOOH M cs
K Na
entry
+ Et1 -% PhCOOEt
solvent DMF DMSO ClCHZCHzCl CeH6 THF CHaCN DMF DMF
Table 11. CsF-Promoted Esterification of Carboxylic Acids"
94 (94) (81) (52) 95 98 (71)
13
Et1 EtOS02CHs EtBr CHz=CHCH2Br PhCH?Br i-PrIc t-BuI' t-BuCH2I EtId Et1 BuI Et1 Et1
14
Me1
80 (94)
15
Me1
74 (78)
16
Me1
90
17
61 (78) 97 100
20
Et1 MeI' MeI' MeIf
21
Et1
90
22
Me1
70
1
yield of PhCOOEt,b % 100 92 0
0 0 0 82 2
a Reaction conditions: benzoic acid (1 mmol), ethyl iodide (2.9 mmol), MF (1.5 mmol), solvent (3 mL), room temperature, 24 h. bBased on GLC.
yield of ester,b %
R'X
RCOOH PhCOOH
2 3
4 5 6 7 8 9 10 11 12
n-C11H&OOH C-CBHllCOOH t-BuCOOH Ph&COOH
(3) (0) (76) (95) (87)
83 (88)
although Clark et al. briefly referred to the superiority of this reagent in the alkylation of phthalimide.2c We report
herein that CsF promotes the alkylation of carboxylic acids smoothly under mild conditions. The present method offers an attractive way to avoid the use of diazomethane which is most commonly used in laboratories but is not suitable for large-scale reactions on account of its toxicity. Additional significance of the CsF method lies in ester formation from organotin carboxylates. These compounds are masked carboxylic acids and frequently employed in amino acid synthesis.lb The direct organotin carboxylate-to-ester transformation, therefore, affords synthetic versatility. Alkylation of Free Carboxylic Acids. First, we screened solvents by employing the reaction between benzoic acid and ethyl iodide at room temperature (Table I). DMF gave the best result and DMSO the next best. Other less polar solvents were completely ineffective. Accordingly, DMF was our choice throughout this study. Table I also shows the results with other alkali metal fluorides. Under the same reaction conditions, NaF gave the ester in only 2% yield. While a good yield was obtained with KF, it is apparent that CsF is better. On the basis of these results, we selected the following standard conditions: carboxylic acidalkyl halide:CsF = 1:1.5:1.5;DMF; 10-15 "C, 24 h (eq 1). The results with RCOOH + R'X
CsF
DMF- RCOOR'
(1)
a variety of carboxylic acids and alkyl halides are summarized in Table 11. The expected esters were generally obtained in reasonable yields except for tert-butyl and neopentyl iodides (entries 7 and 8). No restrictions were found with regard to the carboxylic acids. Bulky substituents do not affect the reaction (entries 11-13), and no isomerization was observed with a,,!?and ,!?,y-unsaturated carboxylic acids (entries 14-16). The optical purities of the a-substituted acids were completely retained (entries 17-21). A variety of functional groups remained intact (entries 22-28). The practical utility of this method was exemplified by large-scale 0-methylation of 7-(tetrahydropyranyloxy)-5heptynoic acid, an important intermediate for the a-side chain of prostaglandins8 (eq 2). The reaction smoothly transformed the acid (6.0 g) to the methyl ester (5.0 g, 79%).9 THPO-COOH
Mel/CsF
THPO-COOMe
(2)
(7) For a review on alkali metal fluoride in organic synthesis, see: Yakobson, G. G.; Akhmetova, N. E. Synthesis 1983, 169. (8) For the diazomethane method: Corey, E. J.; Sachdev, H. S. J . Am.
Chem. SOC.1973,95, 8483.
18 19
23 24
NCCHzCOOH EtIdg t-BuMe2SiO(CHz)llC00H MeIhpi
25
R R R R
26 27 28
= 2-COPh
EtId Me1 Me1 EtIk
= 2-OAc
=4-OAc = 2-COOH
(85)
(79) (87)J
98 86 79 70 (78)'
"Reaction conditions: RCOOH ( 1 mmol), R'X (1.5 mmol), CsF (1.5 mmol), DMF (3 mL), 10-15 O C , 24 h. *Isolated yields; GLC
yields are given in parentheses. 'At 40 "C. dEtI (2.9 mmol). OReaction time (37 h). /Me1 (3.4 mmol). BReaction time (3 h). hMeI (6.8 mmol). 'Reaction time ( 1 h). jHO(CHz)llCOOMewas formed in 2% yields. kEtI (3 mmol); CsF (3 mmol). 'Yield of the diester.
Alkylation of Organotin Compounds.lo Organotin carboxylates were prepared by heating an equimolar mixture of carboxylic acid and hexabutyldistannoxane in refluxing benzene for 3 h. The tributyltin carboxylates obtained by evaporating the benzene were subjected to the alkylation without purification (eq 3).11 A DMF solution RCOOH + f/zBu3SnOSnBu3 benzene
-
Bu3SnOCOR
R'X/CsF
RCOOR' (3)
(9) Conversion of the THP acid to the hydroxy methyl ester by use of p-toluenesulfonicacid in MeOH resulted in contamination of an deny1 compound (10%) shown below: Johnson, C. R.; Penning, T. D. J. Am. Chem. SOC. 1988, 110,4726. Ho(\=
.
d C O O M e
(10) For a related study, see: Sato, T.; Otera, J.; Nozaki, H. Tetra-
hedron Lett. 1989, 30, 2959.
(11) Similar results were obtained when the pure, isolated tributyltin benzoate was used see Experimental Section.
2168 J. Org. Chem., Vol. 57, No. 7, 1992
Notes
Table 111. Eeter Formation from Tributyltin Carboxylates (es 3)' reactn yield of RCOOH R'X timeb ester: ?& PhCOOH Et1 18 94 (99) CH2=CHCH2Br 18 96 (100) C-CGHllCOOH EtBr 24 (91) PhCH=CHCOOH Et1 20 91 19 89
!HAC
Et1
30
91
Et1
25
85
H P h + ,
!HAC
Reaction conditions: RCOOH (1 mmol), (Bu3Sn)20(0.55 mmol), benzene, reflux, 3 h; R'X (1.5 mmol), CsF (1.5 mmol), DMF (3 mL), 30 O C . bTimefor reaction between tributyltin carboxylate and alkyl halide. 'Isolated yields; GLC yields are given in parenthese.
of the carboxylate (1equiv) and the alkyl halide (1.5 equiv) was stirred in the presence of CsF (1.5 equiv) at 30 "C for 18-30 h. Aqueous workup afforded the esters in good to excellent yields as shown in Table 111. It is particularly noteworthy that no racemization was detected with the organotin carboxylates derived from amino acids. The crucial role of CsF is apparent from the observation that exposure of BusSnOCOPh to Et1 in the absence of CsF under similar conditions failed to afford the ethyl ester.12 In summary, CsF is a versatile promoter for the alkylation of carboxylic acids. Although the use of rather long reaction times (24 h usually) and the DMF solvent are necessary, it is evident that the CsF method can replace the diazomethane-based esterification in many cases. The mechanism of this reaction is not yet clear, but it is reasonable to assume that hydrogen bonding plays a key role in the reaction of free carboxylic acids as proposed for KF.2 Since CsF is a g d scavenger of hydrogen halides,13 a wide spectrum of acid-sensitive functions is tolerant of the reaction conditions. On the other hand, the attack of the fluoride ion on the tin atom seems to drive the reaction of the organotin carboxylates. Since protection is a process which deactivates functional groups, direct transformation of protected functions needs special a~tivati0n.l~The overall driving force in the present case is presumably the strong interactions between the fluorine and tin atoms. The strong affinities of fluorine for hydrogen and tin enable these unique alkylation reactions of carboxylic acids. Experimental Section
chased from Tokyo Kasei Kogyo. (S)- and (R)-2-Cyclohexyl-2hydroxyacetic acid and (S)-2-hydroxypropanoicacid were products of Sigma, and other reagents were obtained from Wako Chemicals. These commercially available reagents were used without purification. The following compounds were prepared: 4-acetoxybenzoic acid,15tributyltin benzoate,16 12-(tert-butyldimethylsiloxy)dodecanoic acid [from 12-hydroxydodecanoic acid and tert-butyldimethylsilylchloride:l' IR (neat) 3050,1708 cm-'; 'H NMR (CDCl,) 6 0.04 (8, 6 H), 0.88 (s, 9 H), 1.22-1.34 (m, 14 H), 1.45-1.65 (m, 4 H), 2.33 (t,J = 7.33 Hz, 2 H), 3.59 (t,J = 6.72 Hz, 2 H), 9.80 (br, 1 H)], 7-(tetrahydropyranyloxy)-5-heptynoic acid? 12-(tetrahydropyrany1oxy)octadecanoic acid [from 12hydroxyoctadecanoic acid in 3 steps (i. CH2N2,ii. DHP-H+, iii. 1N NaOH): IR (neat) 3050,1710 cm-'; 'H NMR (CDC1,) 6 0.88 (t, J = 6.71 Hz, 3 H), 1.2-1.9 (m, 34 H), 2.33 (t, J = 7.33 Hz, 2 H), 3.50 (m, 1H), 3.60 (m, 1H), 3.92 (m, 1H), 4.67 (m, 1H), 8.90 (br, 1 HI]. The NMR and IR spectra of the following esters were in complete agreement with those of the authentic samples: ethyl benzoate, ethyl cyanoacetate,diethyl phthalate, ethyl cinnamate (Wako Chemicals), ethyl (S)-2-hydroxypropanoate (Aldrich), benzyl benzoate, isopropyl benzoate, ethyl dodecanoate (Tokyo Kasei Kogyo), allyl benzoate, methyl 2-octynoate (Pfaltz & Bauer), ethyl (S)-N-acetylphenylalanine(Sigma), ethyl cyclohexylcarbo~ylate,'~ ethyl triphenyla~etate,'~ ethyl 2,4,6-trimethylbenzoate,15ethyl 2-bemylbenzoate,16methyl 2-acetc~xybenzoate,~~ methyl 4-a~etoxybenzoate,'~butyl 2,2-dimethy1propanoate,l6 methyl 7-(tetrahydropyranyloxy)-5-heptynoate?and ethyl (SIN-acety1~aline.l~Methyl (E)-a-hexenoate, methyl (E)-3-hexenoate, methyl (S)-2-cyclohexyl-2-hydroxyacetate, methyl (S)-2phenylbutanoate, methyl 1 2 - ( t e t r ~ y ~ p y r a n y l o x y ) ~ d ~ ~ t e , were obtained from and 12-(tert-butyldimethylsiloxy)dodecanoate the corresponding carboxylic acids and CH2N2. Physical data of these methyl esters are given below. Physical Data. Methyl (El-3-hexenoate: IR (neat) 1740 cm-'; 'H NMR (CDCl,) 6 0.99 (t, J = 7.33 Hz, 3 H), 2.05 (m, 2 H), 3.03
(dd,J=1.10,6.59Hz,2H),3.68(s,3H),5.51(dtt,J=1.10,6.59, 15.0 Hz, 1 H), 5.61 (dtt, J = 1.10, 6.23, 15.0 Hz, 1 H). Methyl (E)-2-hexenoate: IR (neat) 1722, 1650 cm-'; 'H NMR (CDCl,) 6 0.93 (t,J = 7.33 Hz, 3 H), 1.48 cm, 2 H), 2.18 (m, 2 H), 3.72 (8, 3 H), 5.82 (d, J = 15.7 Hz,1H), 6.97 (dt, J = 6.97, 15.7 Hz, 1H). Methyl (S)-2-cyclohexyl-2-hydroxyaceta~ [a]=D 29.0' (c 1.02, CHCl,); IR (neat) 3490, 1732 cm-'; 'H NMR (CDCl,) 6 1.1-1.5 (m, 6 H), 1.6-1.8 (m, 5 H), 2.66 (d, J = 6.59 Hz, 1 H), 3.79 (8, 3 H), 4.03 (dd, J = 3.30, 6.59 Hz, 1 H). Methyl (S)-2-phenylbutanoate: [(Y]"D 82.3O (c 1.0, CHCl,); IR (neat) 1730 cm-'; 'H NMR (CDCl,) 6 0.88 (t, J = 7.32 Hz,3 H), 1.80 (m, 1 H), 2.09 (m, 1H), 3.45 (t,J = 7.69 Hz, 1 H), 3.64 ( 8 , 3 H), 7.29 (m, 5 H). Methyl 12-(tetrahydropyranyloxy)odadecanoate: IR (neat) 1724 cm-l; 'H NMR (CDC13)6 0.88 (t,J = 6.22 Hz, 3 H), 1.2-1.9 (m, 34 H), 2.30 (t, J = 7.69 Hz, 2 H), 3.48 (m, 1 H), 3.59 (m, 1 H), 3.66 (s, 3 H), 3.91 (m, 1 H), 4.65 (m, 1H). Methyl 12-(tert-butyldimethylsi1oxy)dodecanoate IR (neat) 1739 cm-'; 'H NMR (CDClJ 6 -0.04 (e, 6 H), 0.80 (s,9 H), 1.15-1.28 (m, 14 H), 1.37-1.58 (m, 4 H), 2.20 (t, J = 7.69 Hz, 2 H),3.50 (t, J = 6.60 Hz, 2 H), 3.57 (8, 3 H). General Procedure for the Preparation of Esters. Re-
action of (S)-N-Acetylphenylalaninewith Ethyl Iodide in the Presence of Cesium Fluoride. A mixture of (S)-N-
AU solventswere purified by standard methods before use. CsF, (E)-2-hexenoic acid, (E)-3-hexenoic acid, 2,2-dimethylpropyl iodide, 12-hydroxydodecanoic acid, 2,4,6-trimethylbenzoicacid, 2-octynoic acid, triphenylacetic acid, (S)-2-phenylbutanoicacid, tris [3-[ (heptafluoropropyl)hydroxymethylene]- (+)-camphoratoleuropium(II1) [EuOlfc),] were obtained from Aldrich Chemical Co. (S)-N-Acetylvalineand 2-methyl-2-propyliodide were pur-
acetylphenylalanine (207 mg, 1mmol), CsF (227 mg, 1.5 mmol), Et1 (234 mg, 1.5 mmol), and DMF (3 mL) was stirred at 15 "C for 24 h. The reaction mixture was combined with aqueous NaHC0, (50 mL) and extracted with EtOAc (100 mL). The organic layer was dried (Na2S04) and evaporated. Column chromatography on silica gel (5050 hexane-EtOAc) gave ethyl (S)-N-acetylphenylalanine(211 mg, 90%, 298% ee determined
(12) Ester formation was effected at higher temperature by treating tributyltin carboxylates with alkyl halides in the presence of a quaternary ammonium halide in refluxing CH&N Vijayaraghavan, S. T.; Balasubramanian, T. R. J. Organomet. Chem. 1985,282,17. See also: Ogawa, T.; Nozaki, M.; Mataui, M. Carbohydr. Res. 1978, 60, C7. (13) Shoda, S.; Mukaiyama, T. Chem. Lett. 1980, 391. (14) For our studies on direct transformation of protected functional groups: Sato,T.; Tada, T.; Otera, J.; Nozaki, H. Tetrahedron Lett. 1989, 30,1665. Sato, T.; Otera, J.; N o d , H. J. Org. Chem. 1990,55,4770 and ref 10.
(15).Raber, D. J.; Gariano, P. Jr.; Brod, A. 0.;Gariano, A.; Guida, W. C.; Guida, A. R.; Herbst, M. D. J. Org. Chem. 1979, 44, 1149. (16) Micro-Biological Laboratories, Inc. Fr. Patent 138635, 1963; Chem. Abstr. 1965,152,16296. Neth. Patent 301027,1963; Chem. Abstr.
1966,64,5139. (17) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. SOC.1972,94,6190. (18) Ono, N.; Yamada, T.; Saito, T.; Tanaka, K.; Kaji, A. Bull. Chem.
SOC.Jpn. 1978,51,2401. (19) Mellon, E. F.; Viola, S. J.; Hoover, S. R. J. Phys. Chem. 1953,57,
607.
J. Org. Chem. 1992,57,2169-2173 by 'H NMR in the presence of Eu(hfc),) having the identical physical data with those of the authentic sample: [a]23D 87.4O (c 1.0, CHCl,) ( [ a I 2 (c , ~1.0, CHCl,) of the authentic sample was 90.9'); mp 91.6-93.3 OC (mp of the authentic sample waa 92.0-94.6 OC); 'H NMR (CDC13)6 1.09 (t,J = 7.33 Hz, 3 H), 1.83 (8, 3 H), 2.97 (m, 2 H), 4.02 (9, J = 7.33 Hz, 2 H), 4.73 (q-like, J = 6.59 Hz,1H), 6.71 (d, J = 7.69 Hz, 1H), 7.0-7.2 (m, 5 H); 13CNMR (CDClJ 6 13.6,22.4,37.4,53.0,60.9,126.5,128.0,128.8,135.8,169.6, 171.5.
Large-Scale Preparation of Methyl 7-(Tetrahydropyrany1oxy)-5-heptynoate from 7-(Tetrahydropyranyloxy)-5-heptynoic Acid and Methyl Iodide. A mixture of 7(tetrahydropyranyloxy)-5-heptynoicacid (6.0 g, 26.4 mmol), CsF (8.8 g, 58 mmol), Me1 (8.2 g, 58 mmol), and DMF (100 mL) was stirred at 30 OC for 18 h. The reaction mixture was extracted with EtOAc and washed with saturated aqueous NaHCO, (100 mL x 3). The organic layer was dried (N%S04)and evaporated to give an oil. Column chromatography on silica gel (955 hexane-EtOAc) of this oil provided methyl 7-(te~ahydropyranylo~)-5heptynoate (5.0 g, 79%) having spectral data identical with those of the authentic sample? General Procedure for the Preparation of Esters from Tributyltin Carboxylatesand Alkyl Halides in the Presence of Cesium Fluoride. A mixture of hexabutyldistannoxane (656 mg, 1.1mmol), (S)-N-acetylphenylalanine (414 mg, 2 mmol), and benzene (30 mL) was heated under refluxed in a Dean-Stark apparatus for 3 h. The benzene was removed under reduced pressure, and DMF (6 mL) waa added. To this solution were added CsF (456 mg, 3 mmol) and Et1 (468 mg, 3 mmol), and the reaction mixture was stirred at 30 OC for 30 h. Aqueous workup as described for reaction of (S)-N-acetylphenylalaninewith ethyl iodide and column chromatography on silica gel (50:50 benzeneEtOAc) afforded ethyl (27)-N-acetylphenylalanine(430 mg, 91%, 198% ee determined by 'H NMR in the presence of Eu(hfc)3): [ajaD88.0° (c 1.0, CHClJ; mp 92.0-94.0 OC. The product was identical in all respects with the authentic sample. Reaction of Tributyltin Benzoate with Ethyl Iodide. A. In the Presence of Cesium Fluoride. A mixture of tributyltin benzoate (411 mg, 1mmol), Et1 (234 mg, 1.5 mmol), CsF (228 mg, 1.5 mmol), and DMF (3 mL) was stirred at 30 OC for 2.5 h. Usual workup gave an oiL GLC analysis of this oil revealed the formation of ethyl benzoate in 95% yield. B. In the Absence of Cesium Fluoride. A mixture of tributyltin benzoate (411 mg, 1mmol), Et1 (234 mg, 1.5 mmol), and DMF (3 mL) was stirred at 30 "C for 19 h. No ethyl benzoate could be detected by GLC analysis. Registry No. CsF, 13400-13-0; KF, 7789-23-3; benzoic acid, 65-85-0; dodecanoic acid, 143-07-7;cyclohexanecarboxylic acid, 98-89-5; phthalic acid, 88-99-3; triphenylacetic acid, 595-91-5; 2,4,6-trimethylbenzoic acid, 480-63-7; (E)-2-hexenoic acid, 13419-69-7; (E)-3-hexenoic acid, 1577-18-0; 2-octynoic acid, 5663-96-7; N-acetylphenylalanine, 2018-61-3; (S)-2-hydroxypropanoic acid, 79-33-4; (R)-a-hydroxycyclohexaneaceticacid, 53585-93-6; (S)-a-hydroxycyclohexaneaceticacid, 61475-31-8; (S)-a-ethylbenzeneaceticacid, 4286-151; ethyl benzoate, 93-89-0; allyl benzoate, 583-04-0; benzyl benzoate, 120-51-4; isopropyl benzoate, 939-48-0; tert-butyl benzoate, 774-65-2; ethyl dodecanoate, 106-33-2;ethyl cyclohexanecarboxylate,3289-28-9; butyl phthalate, 84-74-2; ethyl triphenylacetate, 5467-22-1; ethyl 2,4,6-trimethylbenzoate,1754-55-8; methyl (E)-a-hexenoate, 13894-63-8;methyl (E)-3-hexenoate,13898-61-8;methyl 2-octynoate, 111-12-6;ethyl (S)-2-hydroxypropanoate, 687-47-8;methyl (R)-a-hydroxycyclohexaneacetate,92587-21-8; methyl (S)-ahydroxycyclohexaneacetate, 121099-13-6;ethyl N-acetylphenylalanine, 2361-96-8; methyl 12-(tetrahydropyrany1oxy)octadecanoate, 138982-91-9; ethyl cyanoacetate, 105-56-6; methyl 12(tert-butyldimethylsiloxy)dodecanoate,95841-29-5; ethyl 2benzoxybenzoate, 604-61-5;methyl 2-acetoxybenzoate,580-02-9; methyl Cacetoxybenzoate, 24262-66-6; diethyl phthalate, 84-66-2; 12-(tetrahydroxypyranyloxy)octadecanoic acid, 79967-16-1;cyanoacetic acid, 372-09-8; 12-(tert-butyldimethylsiloxy)dodecanoic acid, 77144-42-4; 2-benzoylbenzoicacid, 85-52-9; 2-acetoxybenzoic acid, 50-78-2;4-acetoxybenzoic acid, 2345-34-8; ethyl iodide, 7503-6; ethyl methaneaulfonate, 62-50-0; ethyl bromide, 7496-4; allyl bromide, 106-95-6;benzyl bromide, 100-39-0; isopropyl iodide,
2169
75-30-9; tert-butyl iodide, 588-17-0; l-iodo-2,2-dimethylpropane, 15501-33-4; butyl iodide, 542-6944; methyl iodide, 74-88-4; 12hydroxydodecanoic acid, 505953; 12-hydroxyoctadecanoic acid, 26164-15-8; 7-(tet106-14-9;methyl (S)-a-ethylbenzeneacetate, rahydropyranyloxy)-5-heptynoicacid, 34506-49-5; methyl 7(tetrahydropyranyloxy)-5-heptynoate,50781-90-3;cinnamic acid, 621-82-9;N-acetylvaline, 96-81-1;ethyl cinnamate, 103-36-6; ethyl N-acetylvaline, 2382-78-7; hexabutyldistannoxane, 56-35-9; tributyltin benzoate, 4342-36-3.
Design, Synthesis, and Characterization of a 'Shopping Basket" Bis-porphyrin. The First Examples of Triply Bridged Closely Interspaced Cofacial Porphyrin Dimers Rafik Karaman, Orn Almarsson, Andrei BlaskB, and Thomas C. Bruice* Department of Chemistry, University of California a t Santa Barbara, Santa Barbara, California 93106 Received November 13,1991
The biscobalt complexes of quadruply bridged closely interspaced 5,10,15,20-tetraphenylporphyrindimers have proven to be effective catalysts for the 4e- reduction of O2 to water when adsorbed onto the disk of a rotating ringdisk electrode or when dissolved in aqueous acidic medium.lT2 From electrochemical and NMR data, we find a linear relationship between the interplanar distance in the porphyrin dimer and the percentage of O2reduced by the 4e- reduction pathway.' By use of molecular dynamics, we find that the triply bridged porphyrin dimer la, as compared to a comparable quadruply bridged porphyrin 2 is more flexible and can reach a shorter interplanar distance. Following the CHARM, modeling design, we have synthesized the fiist triply bridged porphyrin dimer la and we have chosen to name it a "shopping basket" bis-porphyrin. The R group in la was chosen to be m-pyridinesulfonamide because this group proved to effect the smallest possible interplanar distances in the limited family of quadruply bridged dimers that we have studied. In addition, la is a convenient precursor to a water-soluble dimer. Following Lindsey's method: Lewis acid catalyzed (BF3*Et20)high dilution condensation of 3 equiv of abromo-m-tolualdehyde' and 1 equiv of m-tolualdehyde with pyrrole (chloroform, room temperature) followed by in situ tetrachloro-1,4-benzoquinoneoxidation of the intermediate porphyrinogen (chloroform, 60 OC) and separation by chromatography on silica gel using ethyl acetate/hexane (1:lO) as eluent afforded the parent monom(1) (a) Bookser, B. C.; Bruice, T. C. J. Am. Chem. SOC. 1991,113,4208. (b)Karaman, R.; Bruice, T. C. J:.Org. Chem. 1991,56,3470. (c) KaraBruice, T. C.J. Am. Chem. SOC.,in man, R.; Blask6, A.; Almarsson, 0.; press. (d) Karaman, R.; Jeon, S.; Almarsson, 0.; Bruice, T. C. J. Am. Chem. SOC., in press. (2) Collman and co-workerswere the fiist to conceive and practice the idea of effecting four-electron reduction of O2to H20using face-to-face porphyrins. For further information see: (a) Collman, J. P.; Marrocco, M.; Denisevich,P.; Koval, C.; Anson, F. C. J.Electroaml. Chem. 1979, 101, 117. (b) Collman, J. P.; Denisevich, P.; Konai, Y.;Marrocco, M.; Koval, C.; Anson, F. C. J. Am. Chem. SOC.1980,102,6027. (c) Collman, J. P.; Hendricks, N. H.; Leidner, C. R.; Ngameni, E.; L'Her, M. Znorg. Chem. 1988,27,387. (d) Durand, R. R., Jr.; Bencoame, C. S.; Collman, J. P.; Anson, F. C. Zbid. 1983,105,2710. (e) Collman,J. P.; Anaon, F. C.; Bencosme, S.; Chong, A.; Collins,T.; Denisevich, P.; Evitt, E.; Geiger, T.; Ibers, J. A.; Jameson, G.; Konai, Y.; Koval, C.; Meier, K.; Okaley, P.; Pettman, R.; Schmittou, E.; Sessler, J. In Organic Synthesis Today and Tomorrow, Trost, B. M., Hutchinson, C. R., Eds.; Pergamon Press: Oxford, 1981; pp 29-45. (3) Lindsey, J. S.; Wagner, R. W. J. Org. Chem. 1989, 54, 828.
0022-3263/92/1957-2169$03.00/00 1992 American Chemical Society
